MIRDAMETINIB DOSAGE FORMS

Abstract

The present disclosure relates to an oral dosage form, such as a capsule, comprising (a) mirdametinib having a d90 no more than 250 microns, a d50 no more than 50 microns, or both, and (b) one or more pharmaceutically acceptable excipients. These dosage forms are useful in the treatment of tumors and cancers, such as plexiform neurofibromas (PN), plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), high grade glioma (HGG), low grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer, and a cancer that has metastasized to a patient's brain. The disclosure also related to improved dosage regimens for mirdametinib treatments.

Description

1 / 48 MIRDAMETINIB DOSAGE FORMS

[001] This application claims the benefit of the US Provisional Application. No. 63 / 490.626, filed on March 16, 2023, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[002] The present invention relates to an oral dosage form, such as a capsule, comprising (a) mirdametinib with a d90 not exceeding 250 microns, a d50 not exceeding 50 microns, or both, and (b) one or more pharmaceutically acceptable excipients. The invention also relates to improved dosage regimens for mirdametinib treatments. BACKGROUND

[003] Mirdametinib is a small allosteric molecule that targets mitogen-activated protein kinase (MEK).

[004] There is a need for effective treatments to treat inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1). BRIEF SUMMARY OF THE INVENTION

[005] One aspect of the present invention is an oral dosage form comprising (a) mirdametinib with a d90 not exceeding 250 microns and (b) one or more pharmaceutically acceptable excipients. In one embodiment, mirdametinib has a d90 ranging from 50 to 150 microns. In another embodiment, mirdametinib has a d90 ranging from 150 to 250 microns. In yet another embodiment, mirdametinib has a d50 of at most 50 microns. In yet another embodiment, mirdametinib has a d50 ranging from 1 to 25 microns. In yet another embodiment, mirdametinib has a d50 ranging from 25 to 50 microns. In yet another embodiment, mirdametinib has a d50 of at most 30 microns. The oral dosage form may be a solid oral dosage form, such as a capsule or tablet. Petition 870250081868, dated 11 / 09 / 2025, page 9 / 77 2 / 48 (e.g., dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mirdametinib. In another embodiment, the oral dosage form contains 2 mg of mirdametinib.

[006] Another aspect is an oral dosage form comprising (a) mirdametinib with a d50 not exceeding 50 microns and (b) one or more pharmaceutically acceptable excipients. In one embodiment, mirdametinib has a d50 of 1 to 25 microns. In yet another embodiment, mirdametinib has a d50 ranging from 25 to 50 microns. In yet another embodiment, mirdametinib has a d50 of at most 30 microns. The oral dosage form may be a solid oral dosage form, such as a capsule or tablet (e.g., dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mirdametinib. In another embodiment, the oral dosage form contains 2 mg of mirdametinib.

[007] In one embodiment, the dosage form is a capsule prepared by (i) roller compaction of a mixture of mirdametinib and one or more pharmaceutically acceptable excipients and (ii) encapsulation of the compacted mixture in a capsule.

[008] Another aspect is an oral dosage form comprising (a) 1 mg of mirdametinib with a d90 not exceeding 250 microns and (b) one or more pharmaceutically acceptable excipients, wherein the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h of less than 400 ng^h / mL, a Cmax not exceeding 40 ng / mL, or both. In one embodiment, the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h of less than 200 ng^h / mL. In another embodiment, the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h of less than 100 ng^h / mL. In another embodiment, the dosage form provides, after oral administration on the first day of treatment with mirdametinib Petition 870250081868, dated 11 / 09 / 2025, page 10 / 77 3 / 48 day of treatment with mirdametinib, a Cmax not exceeding 32 ng / mL. In another modality, the dosage form provides, after oral administration, on the first day of treatment with mirdametinib, a Cmax not exceeding 30 ng / mL.

[009] Yet another aspect is an oral dosage form comprising (a) 1 mg of mirdametinib with a d50 not exceeding 50 microns and (b) one or more pharmaceutically acceptable excipients, wherein the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h less than 400 ng^h / mL, a Cmax not exceeding 40 ng / mL, or both. In one embodiment, the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h less than 200 ng^h / mL. In another embodiment, the dosage form provides, after oral administration on the first day of treatment with mirdametinib, an AUC0-12h less than 100 ng^h / mL. In another dosage form, after oral administration on the first day of treatment with mirdametinib, the Cmax does not exceed 32 ng / mL.In another dosage form, after oral administration on the first day of treatment with mirdametinib, the Cmax does not exceed 30 ng / mL.

[0010] In one embodiment, the oral dosage form of any embodiment described herein releases at least 80% of its mirdametinib in 15 minutes, as measured according to the USP basket method in 0.1 N HCl (0.1 N aqueous HCl solution) and at 75 rpm.

[0011] Another aspect is a method of treating a human patient (e.g., 2 years or older) who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising the oral administration of an effective amount of one or more oral dosage forms described herein to the patient. In one embodiment, the patient has symptomatic plexiform neurofibromas Petition 870250081868, dated 11 / 09 / 2025, p. 11 / 77 4 / 48 inoperable cos.

[0012] Another aspect is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that is progressing or causing significant morbidity, comprising the oral administration of an effective amount of one or more oral dosage forms described herein to the patient.

[0013] In one embodiment of any of the methods described in this document, the patient has progressive PN (i.e., a 20% increase in PN volume documented by comparison of two MRI scans within a period of 12 months or less prior to the first dose of mirdametinib).

[0014] In one modality of any of the methods described in this document, the patient has PNs that cause significant morbidity.

[0015] In one embodiment of any of the methods described in this document, the patient has head and neck injuries that compromise the airways or major vessels, brachial or lumbar plexus injuries that cause nerve compression and loss of function, injuries that cause major deformity or are significantly disfiguring, extremity injuries that cause limb hypertrophy or loss of function, or painful injuries. In one embodiment, the injuries that cause major deformity or are significantly disfiguring are tumors of the head and neck or those in other areas of the body that cannot be concealed by standard clothing.

[0016] In one modality of any of the methods described in this document, the patient has paravertebral lesions.

[0017] In any of the methods described in this document, the patient has a Lansky performance of Petition 870250081868, dated 11 / 09 / 2025, page 12 / 77 5 / 48 at least 60%.

[0018] In any of the methods described in this document, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following: (a) six or more café-au-lait spots with a diameter > 5 mm in pre-pubertal individuals and > 15 mm in post-pubertal individuals; (b) freckles in the armpit or groin areas; (c) optic glioma; (d) two or more Lisch nodes; (e) a distinct bone lesion (sphenoid bone dysplasia or cortical thinning dysplasia of long bones); and (f) a first-degree relative with NF1.

[0019] In one embodiment of any of the methods described in this document, the patient has a documented constitutional mutation of NF1 in a laboratory certified by the Clinical Laboratory Improvement Amendments / College of American Pathologists.

[0020] In one embodiment of any of the methods described in this document, the patient (a) has one parent diagnosed with NF1 and one or more criteria from (1) to (7) or (b) does not have one parent diagnosed with NF1, but has two or more criteria from (1) to (7): (1) six or more café-au-lait spots larger than 5 mm in diameter in pre-pubertal individuals and larger than 15 mm in diameter in post-pubertal individuals; (2) freckles in the armpit or groin area; (3) two or more neurofibromas of any type or a plexiform neurofibroma; (4) optic pathway glioma; Petition 870250081868, dated 11 / 09 / 2025, page 13 / 77 6 / 48 (5) two or more Lisch nodules in the iris identified by slit-lamp examination or two or more choroidal abnormalities (defined as bright, irregular nodules visualized by optical coherence tomography (OCT) / near-infrared (NIR) reflectance imaging); (6) a distinctive bone lesion (such as sphenoid dysplasia, anterolateral tibial curvature or pseudoarthrosis of a long bone); and (7) a heterozygous pathogenic variant of NF1 with a variant allele fraction of 50% in apparently normal tissue such as white blood cells.

[0021] In one embodiment of any of the methods described in this document, the patient is between 2 and 15 years of age. In another embodiment of any of the methods described in this document, the patient is at least 16 years of age.

[0022] In one embodiment, approximately 2 mg / m2 of mirdametinib is administered to the patient twice daily.

[0023] In another embodiment of any of the methods described herein, (a) for a patient with a body surface area not exceeding 0.69 m2, the patient is initially administered 1 mg of mirdametinib twice daily orally (i.e., a total of 2 mg per day), (b) for a patient with a body surface area of ​​0.7 to 1.04 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally (i.e., a total of 4 mg per day), (c) for a patient with a body surface area of ​​1.05 to 1.49 m2, the patient is initially administered 3 mg of mirdametinib twice daily orally (i.e., a total of 6 mg per day). Petition 870250081868, dated 11 / 09 / 2025, page 14 / 77 7 / 48 mg per day), and (d) for a patient who has a body surface area of ​​at least 1.5 m2, the patient is initially given 4 mg of mirdametinib twice daily orally (i.e., a total of 8 mg per day).

[0024] In another embodiment of any of the methods described herein, (a) for a patient with a body surface area of ​​up to 0.59 m2 or 0.4 to 0.59 m2, the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (d) for a patient with a body surface area of ​​1.0 to 1.19 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily orally, (e) for a patient with a body surface area of ​​1.2 At a depth of 1.39 m2, the patient is initially administered 3 mg of mirdametinib twice daily orally.(f) For a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially administered 3.5 mg of mirdametinib twice daily orally, and (g) For a patient with a body surface area of ​​at least 1.6 m2, the patient is initially administered 4 mg of mirdametinib twice daily orally. In one embodiment, the patient is under 12 years of age. In one embodiment, mirdametinib is administered in the form of one or more tablets. Petition 870250081868, dated 11 / 09 / 2025, page 15 / 77 8 / 48 of the (as one or more dispersible tablets). In another embodiment, mirdametinib is administered as one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing. The tablets may be dispersible tablets. One embodiment is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any patient as described herein), comprising the method of administering mirdametinib described above.

[0025] In another embodiment of any of the methods described herein, (a) for a patient with a body surface area of ​​up to 0.69 m2 or 0.4 to 0.69 m2, the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.7 to 1.04 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​1.05 to 1.49 m2, the patient is initially administered 3 mg of mirdametinib twice daily orally, and (d) for a patient with a body surface area of ​​at least 1.5 m2, the patient is initially administered 4 mg of mirdametinib twice daily orally. In one embodiment, the patient is at least 12 years of age.In one embodiment, mirdametinib is administered in the form of one or more capsules, such as one or more 1 mg capsules, one or more 2 mg capsules, or any combination thereof. An embodiment is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any conforming patient). Petition 870250081868, dated 11 / 09 / 2025, page 16 / 77 9 / 48 described here), comprising the method of administration of mirdametinib described above.

[0026] In another embodiment of any of the methods described herein, (a) for a patient with a body surface area of ​​0.4 to 0.59 m2 (or up to 0.59 m2), the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (d) for a patient with a body surface area of ​​1.0 to 1.39 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily orally, (e) for a patient with a body surface area of For patients with an area of ​​1.4 to 1.59 m2, the patient is initially administered 3 mg of mirdametinib twice daily orally.(f) For a patient with a body surface area of ​​1.6 to 1.69 m2, the patient is initially administered 3.5 mg of mirdametinib twice daily orally, and (g) For a patient with a body surface area of ​​at least 1.7 m2, the patient is initially administered 4 mg of mirdametinib twice daily orally. In one embodiment, the patient is under 12 years of age. In one embodiment, mirdametinib is administered as one or more tablets (as one or more dispersible tablets). In another embodiment, mirdametinib is administered as one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof. Petition 870250081868, dated 11 / 09 / 2025, page 17 / 77 10 / 48 nation of any of the above. The tablets may be dispersible tablets. A modality is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any patient as described herein), comprising the method of administering mirdametinib described above.

[0027] An embodiment is a method of administering mirdametinib to a patient (such as a human patient) in need thereof, by means of oral administration of mirdametinib to the patient, wherein (a) for a patient with a body surface area of ​​0.4 to 0.59 m2 (or up to 0.59 m2), the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (d) for a patient with a body surface area of ​​1.0 to 1.19 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily orally. mg of mirdametinib twice daily orally, (e) for a patient with a body surface area of ​​1.2 to 1.39 m2,(f) For a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially given 3.5 mg of mirdametinib twice daily orally, and (g) For a patient with a body surface area of ​​at least 1.6 m2, the patient is initially given 4 mg of mirdametinib twice daily orally. Petition 870250081868, dated 11 / 09 / 2025, page 18 / 77 11 / 48 mg of mirdametinib twice daily orally. In one embodiment, the patient is under 12 years of age. In one embodiment, mirdametinib is administered as one or more tablets (such as one or more dispersible tablets). In another embodiment, mirdametinib is administered as one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing. The tablets may be dispersible tablets. In one embodiment, mirdametinib may have d50, d90, or both, as described herein. In another embodiment, mirdametinib is administered as a dosage form, such as a tablet (e.g., dispersible tablet) or capsule, as described herein.A modality is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any patient as described herein), comprising the method of administering mirdametinib described above.

[0028] Another embodiment is a method of administering mirdametinib to a patient (as a human patient) in need thereof, by administering mirdametinib orally to the patient, wherein (a) for a patient with a body surface area of ​​0.4 to 0.69 m2 (or up to 0.69 m2), the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.7 to 1.04 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​1.05 to 1.49 m2, the patient is initially administered 3 mg of mirdametinib twice daily orally, and (d) for a patient with a body surface area Petition 870250081868, dated 11 / 09 / 2025, page 19 / 77 In a 12 / 48 embodiment of at least 1.5 m2, the patient is initially administered 4 mg of mirdametinib twice daily orally. In one embodiment, the patient is at least 12 years of age. In one embodiment, mirdametinib is administered in the form of one or more capsules, such as one or more 1 mg capsules, one or more 2 mg capsules, or any combination thereof. An embodiment is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any patient as described herein), comprising the method of administering mirdametinib described above.

[0029] Yet another embodiment is a method of administering mirdametinib to a patient (such as a human patient) in need thereof, by means of oral administration of mirdametinib to the patient, wherein (a) for a patient with a body surface area of ​​0.4 to 0.59 m2 (or up to 0.59 m2), the patient is initially administered 1 mg of mirdametinib twice daily orally, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily orally, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily orally, (d) for a patient with a body surface area of ​​1.0 to 1.39 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily orally, (e) for a patient with a body surface area of ​​1.4 to 1.59 m2,The patient is initially given 3 mg of mirdametinib twice daily orally. Petition 870250081868, dated 11 / 09 / 2025, page 20 / 77 13 / 48 (f) For a patient with a body surface area of ​​1.6 to 1.69 m2, the patient is initially given 3.5 mg of mirdametinib twice daily orally, and (g) For a patient with a body surface area of ​​at least 1.7 m2, the patient is initially given 4 mg of mirdametinib twice daily orally. In one embodiment, the patient is under 12 years of age. In one embodiment, mirdametinib is administered as one or more tablets (as one or more dispersible tablets). In another embodiment, mirdametinib is administered as one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of either of the above. The tablets may be dispersible tablets.A modality is a method of treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) (or any patient as described herein), comprising the method of administering mirdametinib described above.

[0030] In any embodiment of any of the methods described in this document, the maximum daily dose is 4 mg of mirdametinib twice daily.

[0031] In any embodiment of the methods described in this document, during each four-week period, mirdametinib is administered for the first three weeks and discontinued in the last week.

[0032] In any of the methods described herein, where the dosage form is a tablet (such as a dispersible tablet), the tablet or tablets to be administered may first be dispersed in water (such as drinking water) (e.g., about 5 to 10 mL of water) to form an oral suspension, optionally shaken so that no lumps remain, and administered (preferably Petition 870250081868, dated 11 / 09 / 2025, page 21 / 77 14 / 48 (presence within 30 minutes). In some embodiments, one or more oral tablets are dispersed in approximately 5 to 10 mL of water in a container, where the tablets are shaken to ensure no lumps remain in the water. In some embodiments, the oral suspension must be administered over 30 minutes. In some cases, the patient rinses the container with the suspension with more potable water (e.g., approximately 5 to 10 mL of water) and administers it to the patient to ensure the full dose is taken.

[0033] In one embodiment of any of the methods described in this document, the administered dose is reduced due to an adverse event, where the dose is reduced as follows: (a) if the dose at the time of the event is 1 mg of mirdametinib twice daily, then the reduced daily dose is 1 mg administered only in the morning; (b) if the dose at the time of the event is 2 mg of mirdametinib twice daily, then the reduced daily dose is 2 mg administered in the morning and 1 mg administered in the afternoon or evening; (c) if the dose at the time of the event is 3 mg of mirdametinib twice daily, then the reduced daily dose is 2 mg administered twice daily; and (d) if the dose at the time of the event is 4 mg of mirdametinib twice daily, then the reduced daily dose is 3 mg administered twice daily. In one embodiment of any of the methods described herein, the adverse event resulting in dose reduction is acneiform.

[0034] In any embodiment of the methods described herein, the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient, at least partially, based on their Petition 870250081868, dated 11 / 09 / 2025, page 22 / 77 15 / 48 objective response rate, wherein the objective response rate is defined as a decrease of at least 20% in tumor size using centrally read MRI volumetric analysis. In one modality, in step (i), mirdametinib is selected based on a response rate of at least 70%. In another modality, in step (i), mirdametinib is selected based on a response rate of at least 75%. In yet another modality, in step (i), mirdametinib is selected based on a response rate of at least 80%. In yet another modality, in step (i), mirdametinib is selected based on a response rate of at least 85%. In yet another modality, in step (i), mirdametinib is selected based on a response rate of at least 90%. In yet another modality, in stage (i), mirdametinib is selected based on a response rate of at least 95%.

[0035] In one embodiment of any of the methods described in this document, the patient has at least a 20% reduction in the volume of the plexiform neurofibroma, as determined by volumetric magnetic resonance imaging analysis after treatment with mirdametinib.

[0036] In any modality of any of the methods described in this document, the treatment results in a decrease in pain intensity.

[0037] In any modality of any of the methods described in this document, the treatment results in a decrease in pain interference.

[0038] Another aspect is a method for treating a tumor or cancer in a human patient selected from the group consisting of plexiform neurofibromas (PN), plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), Petition 870250081868, dated 11 / 09 / 2025, page 23 / 77 16 / 48 brain cancer and a cancer that has metastasized to the brain of a patient, comprising administering to the patient one or more oral dosage forms comprising mirdametinib, as described herein.

[0039] In some respects, a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 1 mg / m2 to about 10 mg / m2 per day based on mirdametinib free base. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base.

[0040] In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in a single dosage form comprising about 0.1 mg / m2 to about 10 mg / m2 based on mirdametinib free base. In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to about 10 mg per day based on mirdametinib free base.

[0041] In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0042] In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, exhibits high penetration of the blood-brain barrier.

[0043] In some respects, the patient is a human being. In some respects, the human being is older than 2 and younger than 25.

[0044] In some respects, the human has had no prior exposure. Petition 870250081868, dated 11 / 09 / 2025, page 24 / 77 17 / 48 to MEK inhibitors.

[0045] In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as monotherapy to treat the tumor or cancer. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat the tumor or cancer.

[0046] In any of the embodiments described herein, the mirdametinib dose may be administered with one or more 0.5 mg, 1 mg or 2 mg mirdametinib dosage forms or any combination thereof. For example, a 3.5 mg dose may be administered as three 1 mg mirdametinib dosage forms (e.g. tablets) and one 0.5 mg mirdametinib dosage form (e.g. tablet).

[0047] In one embodiment, mirdametinib is supplied as 0.5 or 1 mg mirdametinib tablets (e.g., dispersible tablets). In another embodiment, mirdametinib is supplied as 1 or 2 mg mirdametinib capsules. In yet another embodiment, mirdametinib is supplied as 0.5 or 1 mg mirdametinib tablets (e.g., dispersible tablets) and 1 or 2 mg mirdametinib capsules. BRIEF DESCRIPTION OF THE FIGURES

[0048] Figure 1 is a graph showing the release of mirdametinib according to the USP basket method in 0.1 N HCl and at 75 rpm from 1 mg and 2 mg capsules prepared with mirdametinib from Batches #1 and #2, as described in Example 2.

[0049] Figure 2 is a graph showing the release of mirdametinib according to the USP basket method in 0.1 N HCl and at 75 rpm from 2 mg capsules prepared with mirdametinib from Batches #1, 2 and 3, as described in Example 2. Petition 870250081868, dated 11 / 09 / 2025, page 25 / 77 18 / 48 DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0050] To facilitate understanding of the invention set forth in this document, a number of terms are defined below.

[0051] Generally, the nomenclature used in this document and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described in this document are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning commonly understood by one skilled in the art to which this invention pertains.

[0052] In this descriptive report and the accompanying claims, the singular forms “a”, “an”, “the”, and “the” include plural referents unless the context clearly dictates otherwise. The terms “a” (or “an”), as well as the terms “one or more” and “at least one” may be used interchangeably in this document. In certain respects, the term “a” or “an” means single. In other respects, the term “a” or “an” includes two or more or multiple.

[0053] The term “mirdametinib” refers to the single enantiomer N((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide. The teachings contained in the descriptive report relating to mirdametinib apply equally to pharmaceutically acceptable salts of mirdametinib. For example, the invention of a method for treating neurofibromatosis type 1 (NF1) associated with inoperable plexiform neurofibromas (PN) with mirdametinib also means that a pharmaceutically acceptable salt of mirdametinib can be administered to treat NF1 associated with inoperable PN.

[0054] The term mg / m2se refers to the dose in milligrams per m2 of the patient's body surface area. Petition 870250081868, dated 11 / 09 / 2025, page 26 / 77 19 / 48

[0055] The term “individual” refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms individual and patient are used interchangeably in this document in reference to, for example, a mammalian individual, such as a human individual.

[0056] The term “AUC0-12h” refers to the area under the plasma concentration-time curve from time 0 to the end of 12 hours.

[0057] The term “Cmax” refers to the maximum plasma concentration.

[0058] The term “dispersible,” as used herein, refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) that disintegrates and / or dissolves when combined with water or another potable liquid (e.g., a non-aqueous beverage) or with the individual’s own saliva when placed in the individual’s mouth, with or without the addition of agitation or temperature modification. In some respects, the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet may dissolve almost completely, but some undissolved particles may remain.

[0059] As used in this document, the terms treat, treated, and treating mean both therapeutic and prophylactic treatment or preventive measures, where the objective is to prevent or slow down (reduce) an undesirable physiological condition, disorder, or disease, or to obtain beneficial or desired clinical outcomes. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. Beneficial clinical outcomes or Petition 870250081868, dated 11 / 09 / 2025, page 27 / 77 Desired outcomes include, but are not limited to: symptom relief; a decrease in the severity of a condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; improvement in the state of the condition, disorder, or disease or remission (whether partial or total), if detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an intensification or improvement of the condition, disorder, or disease. Treatment must elicit a clinically significant response without excessive levels of side effects. Treatment must also prolong survival, compared to expected survival if no treatment is received.The term therapeutically effective amount is intended to include the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated. The term therapeutically effective amount refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0060] In certain respects, an individual is successfully treated for a tumor, according to the methods described herein, if the patient shows one or more of the following: a reduction in tumor size; relief of one or more symptoms associated with the specific tumor; a reduction in tumor volume; improvement in quality of life; high progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in disease progression (PD), a high time to progression (TTP) Petition 870250081868, dated 11 / 09 / 2025, page 28 / 77 21 / 48 or any combination thereof. In some respects, nationally or internationally accepted standards of treatment outcomes in a given tumor may be used to determine whether an effective amount of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0061] In certain respects, an individual is successfully treated for cancer, for example, ovarian cancer, according to the methods described in this document if the patient exhibits one or more of the following: a reduction in the number or complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer; reduction in morbidity and mortality; improvement in quality of life; increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof.In some respects, nationally or internationally accepted treatment outcome standards for a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these specific outcomes (e.g., CR, PFS, PR).

[0062] The terms pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, physiologically acceptable carrier, or physiologically acceptable excipient refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is pharmaceutically acceptable in the sense that it is compatible with the other ingredients of a pharmaceutical formulation and suitable for use in Petition 870250081868, dated 11 / 09 / 2025, page 29 / 77 22 / 48 contact with human and animal tissue or organs without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications proportionate to a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0063] The term pharmaceutically acceptable salts refers to relatively non-toxic, inorganic and organic acid addition salts of mirdametinib. These salts can be prepared in situ in the administration vehicle or in the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate salts. See, for example, Berge et al. (1977) Pharmaceutical Salts, J. Pharm. Sci 66:1-19.

[0064] The terms about or approximately mean an acceptable error for a particular value, as determined by one skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term about or approximately means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term about or approximately means Petition 870250081868, dated 11 / 09 / 2025, page 30 / 77 23 / 48 ca within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0065] As used herein, “D50” or “d50”, also known as median diameter, corresponds to the value below which 50% of the particles have a smaller volume diameter. “D90” or “d90” corresponds to the value below which 90% of the particles have a smaller volume diameter. Particle size can be measured using wet standard laser diffraction particle sizing techniques known in the art. An example of an instrument for measuring the particle size of dry powders is the Mastersizer 3000, manufactured by Malvern Panalytical Ltd. (Malvern, UK). As particles are generally not spherical, it is difficult and complex to provide dimensional descriptions of these non-spherical particles. As used herein, “volume diameter” refers to the diameter of a sphere with a volume equal to the non-spherical particle.

[0066] Unless the context requires otherwise, the terms comprise, includes and including are used on the basis and clear understanding that they shall be interpreted inclusively, rather than exclusively, and that each of these words is intended to be interpreted in this way in the interpretation of this patent, including the claims below. II. Oral Dosage Forms

[0067] The oral dosage form contains mirdametinib with a d90 not exceeding 250 microns, a d50 not exceeding 50 microns, or both. In one embodiment, the oral dosage form contains 0.5 mg of mirdametinib, 1.0 mg of mirdametinib, 1.5 mg of mirdametinib, 2.0 mg of mirdametinib, 2.5 mg of mirdametinib, 3.0 mg of mirdametinib, 3.5 mg of mirdametinib, or 4.0 mg of mirdametinib.

[0068] In one embodiment, the oral dosage form contains 0.5 mg of mirdametinib. Petition 870250081868, dated 11 / 09 / 2025, page 31 / 77 24 / 48

[0069] In another embodiment, the oral dosage form contains 1.0 mg of mirdametinib.

[0070] In another embodiment, the oral dosage form contains 2.0 mg of mirdametinib.

[0071] Mirdametinib may be present in a crystalline form in the oral dosage form, such as any of those described in U.S. Patents Nos. 6,960,614, 7,060,856, 11,066,358 and 11,084,780, which are incorporated herein by reference in their entirety. In some respects, the crystalline form of mirdametinib is selected from (a) a crystalline form (Form IV) of mirdametinib having characteristics of an X-ray powder diffraction pattern (XRPD) with peaks at 4.6 ± 0.2, 7.3 ± 0.2 and 14.6 ± 0.2 degrees two theta; (b) a crystalline form (Form I) of mirdametinib with characteristics of an XRPD pattern with peaks at 10.6 ± 0.2, 13.7 ± 0.2, 19.0 ± 0.2 and 23.7 ± 0.2 degrees two theta; and (c) a crystalline form (Form II) of mirdametinib with characteristics of an XRPD pattern with peaks at 5.5 ± 0.2 and 19.6 ± 0.2 degrees two theta.

[0072] In some respects, the crystalline form (Form IV) of mirdametinib has characteristics of an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2 (or 7.2 ± 0.2) and 14.6 ± 0.2 degrees two theta (Form IV). In some respects, the crystalline form of mirdametinib has characteristics of an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2 (or 7.2 ± 0.2), 14.6 ± 0.2 and 25.0 ± 0.2 degrees two theta.

[0073] In some respects, the crystalline form of mirdametinib has characteristics of a differential scanning calorimetry (DSC) profile that does not include endothermy with onset at around 117°C.

[0074] In some respects, the crystalline form of mirdametinib does not contain any amount of Form I or Form II detectable by XRPD and / or DSC. Forms I and II are described in Patent Petition 870250081868, dated 11 / 09 / 2025, page 32 / 77 25 / 48 US No. 6,960,614.

[0075] In some respects, the crystalline form of mirdametinib is anhydrous.

[0076] In some respects, the crystalline form of mirdametinib is Form IV. In some respects, the crystalline form of mirdametinib is essentially pure Form IV (as described in U.S. Patent No. 11,066,358, which is hereby incorporated by reference). Form IV is described in U.S. Patents Nos. 7,060,856 and 11,066,358. In some respects, essentially pure Form IV of mirdametinib exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 3 months under standard storage conditions (15°C-25°C and <65% relative humidity). In some respects, essentially pure Form IV of mirdametinib exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 6 months under standard storage conditions (15°C-25°C and <65% relative humidity).In some respects, the essentially pure Form IV of mirdametinib exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 1 year under standard storage conditions (15°C-25°C and <65% relative humidity).

[0077] In some respects, the XRPD pattern is generated using a PANALYTICAL® X'Pert Pro diffractometer using Ni-filtered Cu Ka radiation (45 kV / 40 mA) and a 0.03° 2Θ degree size with an X'CELERATOR® Real Time Multi-Strip detector, configured (a) on the incident beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°) and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BRUKER® D8® ADVANCE™ system using Cu Ka radiation (40 Petition 870250081868, dated 11 / 09 / 2025, page 33 / 77 26 / 48 kV / 40 mA) and a 0.03° 2Θ degree size with a LYNXEYE™ detector, configured (a) on the incident beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Soller slit, beam knife and (b) on the diffracted beam side as follows: anti-scatter slit (8 mm) and 2.5° Soller slit; where samples are mounted flat on zero-bottom Si wafers. In some respects, the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature rise rate of about 15°C / min.

[0078] The oral dosage form may contain one or more diluents, disintegrants, lubricants, or any combination of any of the foregoing. In one embodiment, the oral dosage form comprises (a) about 0.1% w / w about 5% w / w % w / w of mirdametinib, (b) about 50% w / w about 98% w / w of one or more diluents; (c) about 1% w / w about 10% w / w of one or more disintegrants; and (d) up to about 5% w / w of one or more lubricants.

[0079] Suitable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, dibasic calcium phosphate, and any combination thereof. In one embodiment, the oral dosage form includes the diluent microcrystalline cellulose.

[0080] Suitable disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropylcellulose, alginic acid, and any combination of any of the foregoing. In one embodiment, the oral dosage form includes the disintegrant croscarmellose sodium.

[0081] Suitable lubricants include, but are not limited to, this Petition 870250081868, dated 11 / 09 / 2025, page 34 / 77 27 / 48 magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl dibehenate, talc, and any combination of any of the foregoing. In one embodiment, the oral dosage form includes the lubricant magnesium stearate.

[0082] The oral dosage form may be a capsule, such as a hard gelatin capsule.

[0083] The oral dosage form may comprise one or more pharmaceutically acceptable vehicles. In some respects, the oral dosage form is dispersible. In some respects, the oral dosage form is orodispersible. The oral dosage form may be a tablet, a powder, granules, minitablets, or pellets (also called granules). In some respects, the oral dosage form is a powder. In some respects, the oral dosage form is a dispersible powder. In some respects, a capsule or sachet comprises the dispersible powder. In some respects, the oral dosage form is in the form of granules. In some respects, the granules are dispersible granules. In some respects, a capsule or sachet comprises the dispersible granules. In some respects, the oral dosage form is in the form of minitablets. In some respects, the minitablets are dispersible minitablets. In some respects, a capsule or sachet comprises the dispersible minitablets.In some respects, the oral dosage form is in the form of pellets. In some respects, the pellets are dispersible pellets. In some respects, a capsule or sachet comprises the dispersible pellets.

[0084] In some respects, the oral dosage form is a tablet. In some respects, the tablet is a dispersible tablet. In some respects, the tablet is an orodispersible tablet.

[0085] In some respects, the oral dosage form that is a Petition 870250081868, dated 11 / 09 / 2025, page 35 / 77 28 / 48 dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprise about 0.1 mg to about 20 mg of mirdametinib, wherein each component of the oral dosage form is as follows: (a) about 0.1% by weight to about 7% by weight of mirdametinib; (b) about 50% by weight to about 98% by weight of one or more diluents; (c) about 1% by weight to about 10% by weight of one or more disintegrants; (d) optionally 0% by weight to about 5% by weight of one or more flavoring agents; (e) optionally 0% by weight to about 5% by weight of one or more sweeteners; and (f) optionally 0% by weight to about 5% by weight of one or more lubricants.

[0086] In some respects, the oral dosage form which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprises about 0.1 mg to about 20 mg of mirdametinib, wherein each component of the oral dosage form is as follows: (a) about 0.2% by weight to about 1.5% by weight of mirdametinib; (b) about 75% by weight to about 98% by weight of one or more diluents; (c) about 3% by weight to about 8% by weight of one or more disintegrants; (d) optionally 0% by weight to about 5% by weight of one or more flavoring agents; (e) optionally 0% by weight to about 5% by weight of one or more sweeteners; and (f) optionally 0% by weight to about 5% by weight of one or more lubricants.

[0087] In some respects, the oral dosage form which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprises about 0.1 mg to about 20 mg of mirdametinib, wherein each component of the oral dosage form is as follows: (a) about 0.5% by weight to about 1.2% by weight of mirdametinib; (b) about 85% by weight to about 95% by weight of one or more diluents; (c) about Petition 870250081868, dated 11 / 09 / 2025, page 36 / 77 29 / 48 3.5% by weight to about 6% by weight of one or more disintegrants; (d) optionally 0% by weight to about 2.5% by weight of one or more flavoring agents; (e) optionally 0% by weight to about 2% by weight of one or more sweeteners; and (f) optionally 0.5% by weight to about 2% by weight of one or more lubricants.

[0088] In some respects, the oral dosage form that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprises approximately 0.5 mg of mirdametinib. In some respects, the oral dosage form comprises approximately 1 mg of mirdametinib. In some respects, the oral dosage form that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprises approximately 2 mg of mirdametinib. In some respects, the oral dosage form that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets or dispersible pellets comprises approximately 3 mg of mirdametinib. In some respects, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets, comprises approximately 4 mg of mirdametinib.

[0089] In some respects, at least one of the diluents is selected from microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, and dibasic calcium phosphate. In some respects, at least one of the diluents is microcrystalline cellulose.

[0090] In some respects, at least one of the disintegrants is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropylcellulose, and alginic acid. In some respects, at least one of the disintegrants is croscarmellose sodium. Petition 870250081868, dated 11 / 09 / 2025, page 37 / 77 30 / 48

[0091] In some aspects, at least one of the flavoring agents is selected from among natural or synthetic flavors, including, but not limited to, grape flavor, bubblegum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. In some aspects, at least one of the flavoring agents is grape flavor.

[0092] In some respects, at least one of the sweeteners is selected from sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some respects, at least one of the sweeteners is sucralose.

[0093] In some aspects, at least one of the lubricants is selected from magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate. III. Treatment Methods

[0094] Methods for treating a selected tumor or cancer from the group consisting of plexiform neurofibromas (PN), plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer and a cancer that has metastasized to the brain of a patient, comprising administering to a patient in need of mirdametinib or a pharmaceutically acceptable salt thereof are provided in this document.

[0095] In some aspects of any of the methods here Petition 870250081868, dated 11 / 09 / 2025, page 38 / 77 31 / 48 described, the tumor or cancer is a plexiform neurofibroma. In some aspects, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1.

[0096] In some aspects of any of the methods described here, the tumor or cancer is a high-grade glioma. In some aspects, the high-grade glioma is a primary cancer. In some aspects, the high-grade glioma is a metastatic cancer.

[0097] In some aspects of any of the methods described herein, the tumor or cancer is low-grade ovarian cancer. In some aspects, the tumor or cancer is Langerhans cell histiocytosis. In some aspects, the tumor or cancer is brain cancer. In some aspects, the tumor or cancer is a cancer that has metastasized to the patient's brain, including lung cancer, breast cancer, and melanoma.

[0098] In some aspects of any of the methods described herein, a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally.

[0099] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg / m2 to about 10 mg / m2 per day based on the free base of mirdametinib, about 1.5 mg / m2 to about 9.5 mg / m2 per day based on the free base of mirdametinib, about 2 mg / m2 to about 9 mg / m2 per day based on the free base of mirdametinib, about 2.5 mg / m2 to about 8.5 mg / m2 per day based on the free base of mirdametinib, about 3 mg / m2 to about 8 mg / m2 per day based on the free base of mirdametinib, about 3.5 mg / m2 to about 7.5 mg / m2 per day based on the free base of Mirdametinib, approximately 4 mg / m2 to approximately 7 mg / m2 per day based on the free base of mirdametinib, approximately 4.5 Petition 870250081868, dated 11 / 09 / 2025, page 39 / 77 32 / 48 mg / m2a approximately 6.5 mg / m2 per day based on the free base of mirdametinib, or approximately 5 mg / m2a approximately 6 mg / m2 per day based on the free base of mirdametinib. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of approximately 1 mg / m² per day based on mirdametinib free base, approximately 1.5 mg / m² per day based on mirdametinib free base, approximately 2 mg / m² per day based on mirdametinib free base, approximately 2.5 mg / m² per day based on mirdametinib free base, approximately 3 mg / m² per day based on mirdametinib free base, approximately 3.5 mg / m² per day based on mirdametinib free base, approximately 4 mg / m² per day based on mirdametinib free base, approximately 4.5 mg / m² per day based on mirdametinib free base, approximately 5 mg / m² per day based on mirdametinib free base, approximately 5.5 mg / m2 per day based on mirdametinib free base.Approximately 6 mg / m² per day based on mirdametinib free base, approximately 6.5 mg / m² per day based on mirdametinib free base, approximately 7 mg / m² per day based on mirdametinib free base, approximately 7.5 mg / m² per day based on mirdametinib free base, approximately 8 mg / m² per day based on mirdametinib free base, approximately 8.5 mg / m² per day based on mirdametinib free base, approximately 9 mg / m² per day based on mirdametinib free base, approximately 9.5 mg / m² per day based on mirdametinib free base, or approximately 10 mg / m² per day based on mirdametinib free base.

[00100] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg to about 10 mg per day based on the mirdametinib free base, about 1.5 mg to about 9.5 mg per day based on the mirdametinib free base, about 2 mg to about 9 mg per day based on the Petition 870250081868, dated 11 / 09 / 2025, p. 40 / 77 33 / 48 mirdametinib free base, approximately 2.5 mg to approximately 8.5 mg per day based on mirdametinib free base, approximately 3 mg to approximately 8 mg per day based on mirdametinib free base, approximately 3.5 mg to approximately 7.5 mg per day based on mirdametinib free base, approximately 4 mg to approximately 7 mg per day based on mirdametinib free base, approximately 4.5 mg to approximately 6.5 mg per day based on mirdametinib free base, or approximately 5 mg to approximately 6 mg per day based on mirdametinib free base.In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of approximately 1 mg per day based on mirdametinib free base, approximately 1.5 mg per day based on mirdametinib free base, approximately 2 mg per day based on mirdametinib free base, approximately 2.5 mg per day based on mirdametinib free base, approximately 3 mg per day based on mirdametinib free base, approximately 3.5 mg per day based on mirdametinib free base, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately mirdametinib, approximately Mirdametinib, approximately mirdametinib, approximately mg per day with 4.5 mg per day with 5 mg per day with 5.5 mg per day with 6 mg per day with 6.5 mg per day with 7 mg per day with. 7.5 mg per day with 8 mg per day with 8.5 mg per day with 9 mg per day with 9.5 mg per day based on freebase mirdametinib, or approximately 10 mg per day based on freebase mirdametinib.

[00101] In some aspects of any of the methods described in Petition 870250081868, dated 11 / 09 / 2025, page 41 / 77 34 / 48 of this document, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising approximately 0.1 mg / m2 to approximately 10 mg / m2 based on the free base of mirdametinib, approximately 0.5 mg / m2 to approximately 9.5 mg / m2 based on the free base of mirdametinib, approximately 1 mg / m2 to approximately 9 mg / m2 based on the free base of mirdametinib, approximately 1.5 mg / m2 to approximately 8.5 mg / m2 based on the free base of mirdametinib, approximately 2 mg / m2 to approximately 8 mg / m2 based on the free base of mirdametinib, approximately 2.5 mg / m2 to approximately 7.5 mg / m2 based on the free base of mirdametinib, approximately 3 mg / m2 to approximately 7 mg / m2 based on the free base of mirdametinib, approximately 3.5 mg / m2 to approximately 6.5 mg / m2 based on the free base of mirdametinib, approximately 4 mg / m2 to approximately 6 mg / m2 based on the free base of mirdametinib, or approximately 4.5 mg / m2 to approximately 5.5 mg / m2 based on the free base of mirdametinib. In some respects, mirdametinib,or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising approximately 0.1 mg / m2 based on mirdametinib free base, approximately 0.2 mg / m2 based on mirdametinib free base, approximately 0.3 mg / m2 based on mirdametinib free base, approximately 0.4 mg / m2 based on mirdametinib free base, approximately 0.5 mg / m2 based on mirdametinib free base, approximately 1 mg / m2 based on mirdametinib free base, approximately 1.5 mg / m2 based on mirdametinib free base, approximately 2 mg / m2 based on mirdametinib free base, approximately 2.5 mg / m2 based on mirdametinib free base, approximately 3 mg / m2 based on mirdametinib free base, approximately 3.5 mg / m2 based on mirdametinib free base, approximately 4 mg / m2 based on mirdametinib free base, approximately 4.5 mg / m2 based on mirdametinib free base, approximately 5 mg / m2 based on mirdametinib free base, approximately 5.5 mg / m2 based on mirdametinib free base, Petition 870250081868, dated 11 / 09 / 2025, page 42 / 77 35 / 48 approximately 6 mg / m2 based on mirdametinib free base, approximately 6.5 mg / m2 based on mirdametinib free base, approximately 7 mg / m2 based on mirdametinib free base, approximately 7.5 mg / m2 based on mirdametinib free base, approximately 8 mg / m2 based on mirdametinib free base, approximately 8.5 mg / m2 based on mirdametinib free base, approximately 9 mg / m2 based on mirdametinib free base, approximately 9.5 mg / m2 based on mirdametinib free base, or approximately 10 mg / m2 based on mirdametinib free base.

[00102] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on the mirdametinib free base, about 0.5 mg to about 9.5 mg based on the mirdametinib free base, about 1 mg to about 9 mg based on the mirdametinib free base, about 1.5 mg to about 8.5 mg based on the mirdametinib free base, about 2 mg to about 8 mg based on the mirdametinib free base, about 2.5 mg to about 7.5 mg based on the mirdametinib free base, about 3 mg to about 7 mg based on the mirdametinib free base, about 3.5 mg to about 6.5 mg based on the mirdametinib free base. mg based on the free base of mirdametinib, approximately 4 mg to approximately 6 mg based on the free base of mirdametinib, or approximately 4.5 mg to approximately 5.5 mg based on the free base of mirdametinib.In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising approximately 0.1 mg based on mirdametinib free base, approximately 0.2 mg based on mirdametinib free base, approximately 0.3 mg based on mirdametinib free base, approximately 0.4 mg based on mirdametinib free base, approximately 0.5 mg based on mirdametinib free base, approximately 1 mg. Petition 870250081868, dated 11 / 09 / 2025, page 43 / 77 36 / 48 based on mirdametinib free base, approximately 1.5 mg based on mirdametinib free base, approximately 2 mg based on mirdametinib free base, approximately 2.5 mg based on mirdametinib free base, approximately 3 mg based on mirdametinib free base, approximately 3.5 mg based on mirdametinib free base, approximately 4 mg based on mirdametinib free base, approximately 4.5 mg based on mirdametinib free base, approximately 5 mg based on mirdametinib free base, approximately 5.5 mg based on mirdametinib free base, approximately 6 mg based on mirdametinib free base, approximately 6.5 mg based on mirdametinib free base, approximately 7 mg based on mirdametinib free base mirdametinib, approximately 7.5 mg based on mirdametinib free base, approximately 8 mg based on mirdametinib free base, approximately 8.5 mg based on mirdametinib free base, approximately 9 mg based on mirdametinib free base, approximately 9,5 mg based on mirdametinib freebase or approximately 10 mg based on mirdametinib freebase.

[00103] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered once, twice, three, or four times daily. In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some aspects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[00104] In some aspects of any of the methods described in this document, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of about 0.5 mg / m2 to about 10 mg / m2 based on the free base of mirdametinib, about 1 mg / m2 to about 9.5 mg / m2 based on the free base of mirdametinib, about 1.5 mg / m2 to about 9 Petition 870250081868, dated 11 / 09 / 2025, p. 44 / 77 37 / 48 mg / m2 based on mirdametinib free base, approximately 2 mg / m2 to approximately 8.5 mg / m2 based on mirdametinib free base, approximately 2.5 mg / m2 to approximately 8 mg / m2 based on mirdametinib free base, approximately 3 mg / m2 to approximately 7.5 mg / m2 based on mirdametinib free base, approximately 3.5 mg / m2 to approximately 7 mg / m2 based on mirdametinib free base, approximately 4 mg / m2 to approximately 6.5 mg / m2 based on mirdametinib free base, approximately 4.5 mg / m2 to approximately 6 mg / m2 based on mirdametinib free base, or approximately 5 mg / m2 to approximately 6 mg / m2 based on mirdametinib free base. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of approximately 0.5 mg / m2 based on mirdametinib free base, approximately 1 mg / m2 based on mirdametinib free base, approximately 1.5 mg / m2 based on mirdametinib free base, approximately 2 mg / m2 based on mirdametinib free base, approximately 2 mg / m2 based on mirdametinib free base.5 mg / m2 based on mirdametinib free base, approximately 3 mg / m2 based on mirdametinib free base, approximately 3.5 mg / m2 based on mirdametinib free base, approximately 4 mg / m2 based on mirdametinib free base, approximately 4.5 mg / m2 based on mirdametinib free base, approximately 5 mg / m2 based on mirdametinib free base, approximately 5.5 mg / m2 based on mirdametinib free base, approximately 6 mg / m2 based on mirdametinib free base, approximately 6.5 mg / m2 based on mirdametinib free base, approximately 7 mg / m2 based on mirdametinib free base, approximately 7.5 mg / m2 based on mirdametinib free base, approximately 8 mg / m2 based on mirdametinib free base, approximately 8.5 mg / m2 based on mirdametinib free base, approximately 9 mg / m2 based on mirdametinib free base, approximately 9.5 mg / m2 based on mirdametinib free base, or approximately 10 mg / m2 based on mirdametinib free base. Petition 870250081868, dated 11 / 09 / 2025, page 45 / 77 38 / 48

[00105] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of about 0.5 mg to about 10 mg based on the mirdametinib free base, about 1 mg to about 9.5 mg based on the mirdametinib free base, about 1.5 mg to about 9 mg based on the mirdametinib free base, about 2 mg to about 8.5 mg based on the mirdametinib free base, about 2.5 mg to about 8 mg based on the mirdametinib free base, about 3 mg to about 7.5 mg based on the mirdametinib free base, about 3.5 mg to about 7 mg based on the mirdametinib free base, about 4 mg to about 6.5 mg with Based on the free base of mirdametinib, approximately 4.5 mg to approximately 6 mg based on the free base of mirdametinib, or approximately 5 mg to approximately 6 mg based on the free base of mirdametinib. In some respects, mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twice daily in amounts of approximately 0.5 mg based on mirdametinib freebase, approximately 1 mg based on mirdametinib freebase, approximately 1.5 mg based on mirdametinib freebase, approximately 2 mg based on mirdametinib freebase, approximately 2.5 mg based on mirdametinib freebase, approximately 3 mg based on mirdametinib freebase, approximately 3.5 mg based on mirdametinib freebase, approximately 4 mg based on mirdametinib freebase, approximately 4.5 mg based on mirdametinib freebase, approximately 5 mg based on mirdametinib freebase, approximately 5.5 mg based on mirdametinib freebase, approximately 6 mg based on mirdametinib freebase. mirdametinib, approximately 6.5 mg based on mirdametinib free base, approximately 7 mg based on mirdametinib free base, approximately 7.5 mg based on mirdametinib free base, approximately 8 mg based on mirdametinib free base, Petition 870250081868, dated 11 / 09 / 2025, page 46 / 77 39 / 48 be, approximately 8.5 mg based on mirdametinib free base, approximately 9 mg based on mirdametinib free base, approximately 9.5 mg based on mirdametinib free base, or approximately 10 mg based on mirdametinib free base.

[00106] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a total daily dose not exceeding about 10 mg / m2 based on the free base of mirdametinib, about 9.5 mg / m2 based on the free base of mirdametinib, about 9 mg / m2 based on the free base of mirdametinib, about 8.5 mg / m2 based on the free base of mirdametinib, about 8 mg / m2 based on the free base of mirdametinib, about 7.5 mg / m2 based on the free base of mirdametinib, about 7 mg / m2 based on the free base of mirdametinib, about 6.5 mg / m2 based on the free base of mirdametinib, about 6 mg / m2 based on the free base of mirdametinib, about 5.5 mg / m2 based on mirdametinib free base, about 5 mg / m2 based on mirdametinib free base, about 4.5 mg / m2 based on mirdametinib free base, about 4 mg / m2 based on mirdametinib free base, about 3.5 mg / m2 based on mirdametinib free base, approximately 3 mg / m2 based on mirdametinib free base, approximately 2.5 mg / m2 based on mirdametinib free base, approximately 2 mg / m2 based on mirdametinib free base, approximately 1.5 mg / m2 based on mirdametinib free base.

[00107] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a total daily dose not exceeding about 10 mg based on the mirdametinib free base, about 9.5 mg based on the mirdametinib free base, about 9 mg based on the mirdametinib free base, about 8.5 mg with Petition 870250081868, dated 11 / 09 / 2025, page 47 / 77 40 / 48 based on mirdametinib free base, approximately 8 mg based on mirdametinib free base, approximately 7.5 mg based on mirdametinib free base, approximately 7 mg based on mirdametinib free base, approximately 6.5 mg based on mirdametinib free base, approximately 6 mg based on mirdametinib free base, approximately 5.5 mg based on mirdametinib free base, approximately 5 mg based on mirdametinib free base, approximately 4.5 mg based on mirdametinib free base, approximately 4 mg based on mirdametinib free base, approximately 3.5 mg based on mirdametinib free base, approximately 3 mg based on mirdametinib free base, approximately 2.5 mg based on mirdametinib free base, Approximately 2 mg based on the free base of mirdametinib, or approximately 1.5 mg based on the free base of mirdametinib.

[00108] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as mirdametinib freebase.

[00109] Methods for treating a tumor or cancer selected from the group consisting of plexiform neurofibromas (PN), plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer and a cancer that has metastasized to the brain of a patient, comprising administering to a patient in need thereof the mirdametinib freebase are provided herein.

[00110] In some aspects of any of the methods described herein, the tumor or cancer is a plexiform neurofibroma. In some aspects, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1.

[00111] In some aspects of any of the methods described here, the tumor or cancer is a high-grade glioma. In some cases, the Petition 870250081868, dated 11 / 09 / 2025, page 48 / 77 41 / 48 aspects, high-grade glioma is a primary cancer. In some aspects, high-grade glioma is a metastatic cancer.

[00112] In some aspects of any of the methods described here, the tumor or cancer is low-grade ovarian cancer.

[00113] In some aspects of any of the methods described here, the tumor or cancer is Langerhans cell histiocytosis.

[00114] In some aspects of any of the methods described here, the tumor or cancer is brain cancer.

[00115] In some aspects of any of the methods described here, the tumor or cancer is a cancer that has metastasized to the patient's brain, including lung cancer, breast cancer, and melanoma.

[00116] In some aspects of any of the methods described here, a therapeutically effective amount of mirdametinib freebase is administered.

[00117] In some aspects of any of the methods described herein, the free base of mirdametinib is administered in an amount of approximately 1 mg / m2 to approximately 10 mg / m2 per day, approximately 1.5 mg / m2 to approximately 9.5 mg / m2 per day, approximately 2 mg / m2 to approximately 9 mg / m2 per day, approximately 2.5 mg / m2 to approximately 8.5 mg / m2 per day, approximately 3 mg / m2 to approximately 8 mg / m2 per day, approximately 3.5 mg / m2 to approximately 7.5 mg / m2 per day, approximately 4 mg / m2 to approximately 7 mg / m2 per day, approximately 4.5 mg / m2 to approximately 6.5 mg / m2 per day, or approximately 5 mg / m2 to approximately 6 mg / m2 per day. In some respects, the free base of mirdametinib is administered in an amount of approximately 1 mg / m² per day, approximately 1.5 mg / m² per day, approximately 2 mg / m² per day, approximately 2.5 mg / m² per day, approximately 3 mg / m² per day, approximately 3.5 mg / m² per day, approximately 4 mg / m² per day, approximately 4.5 mg / m² per day, approximately 5 mg / m² per day, approximately 5.5 mg / m² per day, approximately 6 mg / m² per day, approximately 6.5 mg / m² per day, approximately 7 mg / m² per day, approximately 7.5 mg / m² per day. Petition 870250081868, dated 11 / 09 / 2025, page 49 / 77 42 / 48 day, approximately 8 mg / m2 per day, approximately 8.5 mg / m2 per day, approximately 9 mg / m2 per day, approximately 9.5 mg / m2 per day, or approximately 10 mg / m2 per day.

[00118] In some aspects of any of the methods described in this document, the mirdametinib free base is administered in an amount of about 1 mg to about 10 mg per day, about 1.5 mg to about 9.5 mg per day, about 2 mg to about 9 mg per day, about 2.5 mg to about 8.5 mg per day, about 3 mg to about 8 mg per day, about 3.5 mg to about 7.5 mg per day, about 4 mg to about 7 mg per day, about 4.5 mg to about 6.5 mg per day, or about 5 mg to about 6 mg per day.In some respects, the free base of mirdametinib is administered in an amount of approximately 1 mg per day, approximately 1.5 mg per day, approximately 2 mg per day, approximately 2.5 mg per day, approximately 3 mg per day, approximately 3.5 mg per day, approximately 4 mg per day, approximately 4.5 mg per day, approximately 5 mg per day, approximately 5.5 mg per day, approximately 6 mg per day, approximately 6.5 mg per day, approximately 7 mg per day, approximately 7.5 mg per day, approximately 8 mg per day, approximately 8.5 mg per day, approximately 9 mg per day, approximately 9.5 mg per day, or approximately 10 mg per day.

[00119] In some aspects of any of the methods described herein, the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg / m2 to about 10 mg / m2, about 0.5 mg / m2 to about 9.5 mg / m2, about 1 mg / m2 to about 9 mg / m2, about 1.5 mg / m2 to about 8.5 mg / m2, about 2 mg / m2 to about 8 mg / m2, about 2.5 mg / m2 to about 7.5 mg / m2, about 3 mg / m2 to about 7 mg / m2, about 3.5 mg / m2 to about 6.5 mg / m2, about 4 mg / m2 to about 6 mg / m2, or about 4.5 mg / m2 to about 5.5 mg / m2. In some respects, the free base of mirdametinib is administered in a single-dose form comprising approximately 0.1 mg / m2, approximately 0.2 Petition 870250081868, dated 11 / 09 / 2025, page 50 / 77 43 / 48 mg / m2, about 0.3 mg / m2, about 0.4 mg / m2, about 0.5 mg / m2, about 1 mg / m2, about 1.5 mg / m2, about 2 mg / m2, about 2.5 mg / m2, about 3 mg / m2, about 3.5 mg / m2, about 4 mg / m2, about 4.5 mg / m2, about 5 mg / m2, about 5.5 mg / m2, about 6 mg / m2, about 6.5 mg / m2, about 7 mg / m2, about 7.5 mg / m2, about 8 mg / m2, about 8.5 mg / m2, about 9 mg / m2, about 9.5 mg / m2, or about 10 mg / m2.

[00120] In some aspects of any of the methods described in this document, the mirdametinib free base is administered in a single dosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg to about 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg, about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg, or about 4.5 mg to about 5.5 mg.In some respects, the free base of mirdametinib is administered in a single dosage form comprising approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 1 mg, approximately 1.5 mg, approximately 2 mg, approximately 2.5 mg, approximately 3 mg, approximately 3.5 mg, approximately 4 mg, approximately 4.5 mg, approximately 5 mg, approximately 5.5 mg, approximately 6 mg, approximately 6.5 mg, approximately 7 mg, approximately 7.5 mg, approximately 8 mg, approximately 8.5 mg, approximately 9 mg, approximately 9.5 mg, or approximately 10 mg.

[00121] In some aspects of any of the methods described in this document, the mirdametinib free base is administered once, twice, three, or four times daily. In some aspects, the mirdametinib free base is administered once daily. In some aspects, the mirdametinib free base is administered twice daily.

[00122] In some aspects of any of the methods described in Petition 870250081868, dated 11 / 09 / 2025, page 51 / 77 44 / 48 present document, a base livre de mirdametinibe é administrada duas vezes ao dia em uma quantidade de cerca de 0.5 mg / m2a cerca de 10 mg / m2, cerca de 1 mg / m2a cerca de 9.5 mg / m2, cerca de 1.5 mg / m2a cerca de 9 mg / m2, cerca de 2 mg / m2a cerca de 8.5 mg / m2, cerca de 2.5 mg / m2a cerca de 8 mg / m2, cerca de 3 mg / m2a cerca de 7.5 mg / m2, cerca de 3.5 mg / m2a cerca de 7 mg / m2, cerca de 4 mg / m2a cerca de 6.5 mg / m2, cerca de 4.5 mg / m2a cerca de 6 mg / m2, ou cerca de 5 mg / m2a cerca de 6 mg / m2. In some aspects, the free base of mirdametinibe is administered twice a day in a quantity of about 0.5 mg / m2a about 1 mg / m2, about 1.5 mg / m2a about 2 mg / m2, about 2.5 mg / m2a about 3 mg / m2, about 3.5 mg / m2a about 4 mg / m2, about 4.5 mg / m2a about 5 mg / m2, about 5.5 mg / m2a about 6 mg / m2, about 6.5 mg / m2a about 7 mg / m2, about 7.5 mg / m2a about 8 mg / m2, about 8.5 mg / m2a about 9 mg / m2, about 9.5 mg / m2, or about 10 mg / m2.

[00123] In some aspects of any of the methods described in this document, the mirdametinib free base is administered twice in amounts of about 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg, about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg to about 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg, about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, about 5 mg to about 6 mg. In some respects, the free base of mirdametinib is administered twice daily in amounts of approximately 0.5 mg to approximately 1 mg, approximately 1.5 mg, approximately 2 mg, approximately 2.5 mg, approximately 3 mg, approximately 3.5 mg, approximately 4 mg, approximately 4.5 mg, approximately 5 mg, approximately 5.5 mg, approximately 6 mg, approximately 6.5 mg, approximately 7 mg, approximately 7.5 mg, approximately 8 mg, approximately 8.5 mg, approximately 9 mg, approximately 9.5 mg, or approximately 10 mg.

[00124] In some aspects of any of the methods described in Petition 870250081868, dated 11 / 09 / 2025, page 52 / 77 45 / 48 herein, mirdametinib free base is administered at a total daily dose that does not exceed about 10 mg / m2, about 9.5 mg / m2, about 9 mg / m2, about 8.5 mg / m2, about 8 mg / m2, about 7.5 mg / m2, about 7 mg / m2, about 6.5 mg / m2, about 6 mg / m2, about 5.5 mg / m2, about 5 mg / m2, about 4.5 mg / m2, about 4 mg / m2, about 3.5 mg / m2, about 3 mg / m2, about 2.5 mg / m2, about 2 mg / m2, or about 1.5 mg / m2.

[00125] In some aspects of any of the methods described in this document, the mirdametinib free base is administered at a total daily dose not exceeding about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.

[00126] In some aspects of any of the methods described in this document, mirdametinib, or a pharmaceutically acceptable salt thereof, exhibits high penetration of the blood-brain barrier.

[00127] In some aspects of any of the methods described in this document, the patient is a human being.

[00128] In some aspects of any of the methods described in this document, the human is between 2 and 25 years old. In some aspects, the human is between 2 and 18 years old.

[00129] In some aspects of any of the methods described herein, the human has had no prior exposure to MEK inhibitors. In some aspects, the human has not responded to prior treatment with one or more MEK inhibitors.

[00130] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally. In some aspects, Petition 870250081868, dated 11 / 09 / 2025, page 53 / 77 46 / 48 Mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally as a solid dosage form. In some respects, the solid dosage form is a tablet or capsule. In some respects, the solid dosage form is a capsule. In some respects, mirdametinib, or a pharmaceutically acceptable salt thereof, is dispersible in a drinkable liquid or orodispersible in the patient's saliva.

[00131] In some aspects of any of the methods described in this document, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as monotherapy to treat the tumor or cancer.

[00132] In some aspects of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat the tumor or cancer. EXAMPLE Example 1

[00133] Mirdametinib-free base (Lots #1, 2 and 3) was prepared with the properties in the table below. Property Drug Substance Lot 1 Drug Substance Lot 2 Drug Substance Lot 3 D10 (pm) 4.9 7.6 17.8 D50 (pm) 20.9 28.4 46.5 D90 (pm) 101.5 120.7 217.1 Crude Density (g / mL) 0.169 0.197 - Compacted Density (g / mL) 0.394 0.434 - Carr Index 57.1 54.6 - Example 2

[00134] 1 and 2 mg capsules with the formulations described in the table below were prepared using one of Lots #1 and 2 of ExemPetition 870250081868, dated 11 / 09 / 2025, page 54 / 77 47 / 48 plo 1. The ingredients were mixed and compacted by roller before being encapsulated in capsules (opaque hard gelatin capsules, size 3). Ingredient Function 1 mg Capsule 2 mg Capsule % w / w mg / capsule % w / w mg / capsule Mirdametinib Active Ingredient 0.77 1.0 0.77 2.0 Microcrystalline Cellulose Diluent 93.23 121.2 93.23 242.4 Croscarmellose Sodium Disintegrant 5.00 6.5 5.00 13.0 Magnesium Stearate Lubricant 1.00 1.3 1.00 2.6 Total 100 130.0 100 260.0

[00135] The dissolution of the 1 mg and 2 mg capsules prepared with mirdametinib from Lots #1 and #2 was measured according to the USP basket method in 0.1 N HCl (0.1 N aqueous HCl solution) at 75 rpm, and is shown in Figure 1. As shown, the tested capsules released more than 80% of the mirdametinib in 15 minutes.

[00136] 2 mg capsules with the formulation provided above were prepared from Lot #3. The dissolution of the 2 mg capsules prepared from Lots #1, 2 and 3 was measured according to the USP basket method in 0.1 N HCl at 75 rpm, and is shown in Figure 2. As shown, the tested capsules released more than 80% of the mirdametinib in 15 minutes.

[00137] All publications, patents and patent applications mentioned in this descriptive report are incorporated herein by reference in their entirety, to the same extent as if each individual publication, patent or patent application were specifically and individually indicated for incorporation. Petition 870250081868, dated 11 / 09 / 2025, page 55 / 77 48 / 48 by way of reference in its entirety. When a term in this application is deemed to be defined differently in a document incorporated herein by reference, the definition given herein shall serve as the definition for the term.

[00138] Although the invention has been described in connection with specific aspects thereof, it will be understood that the invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations that, in general, are within the known or customary practice of the art to which the invention belongs and may be applied to the essential features set forth below and within the scope of the claim. Petition 870250081868, dated 11 / 09 / 2025, pp. 56 / 77

Claims

1 / 10 CLAIMS 1. Oral dosage form, characterized in that it comprises (a) mirdametinib having a d90 of not more than 250 microns and (b) one or more pharmaceutically acceptable excipients.

2. Oral dosage form, according to claim 1, characterized in that mirdametinib has a d50 of not more than 50 microns.

3. Oral dosage form, according to any of the preceding claims, characterized in that mirdametinib has a d50 of no more than 30 microns.

4. Oral dosage form according to any one of claims 1 to 3, characterized in that the dosage form is a capsule prepared by (i) roller compaction of a mixture of mirdametinib and one or more pharmaceutically acceptable excipients and (ii) encapsulation of the compacted mixture in a capsule.

5. Oral dosage form, characterized in that it comprises (a) 1 mg of mirdametinib having a d90 of not more than 250 microns and (b) one or more pharmaceutically acceptable excipients, wherein the dosage form provides, upon oral administration, on the first day of treatment with mirdametinib, an AUC0-12h of less than 400 ng^h / mL, a Cmax not exceeding 40 ng / mL, or both.

6. Oral dosage form, according to claim 5, characterized in that the dosage form provides, upon oral administration, on the first day of treatment with mirdametinib, an AUC0-12h of less than 200 ng^h / mL.

7. Oral dosage form, according to claim 5, characterized in that the dosage form provides, upon oral administration, on the first day of treatment with mirdametinib, an AUC0-12h of less than 100 ng^h / mL. Petition 870250081868, dated 11 / 09 / 2025, pp. 57 / 77 2 / 10 8. Oral dosage form, according to any one of claims 5 to 7, characterized in that the dosage form provides, upon oral administration, on the first day of treatment with mirdametinib, a Cmax of not more than 32 ng / mL.

9. Oral dosage form, according to any one of claims 5 to 7, characterized in that the dosage form provides, upon oral administration, on the first day of treatment with mirdametinib, a Cmax of not more than 30 ng / mL.

10. Oral dosage form, according to any of the preceding claims, characterized in that the dosage form is a capsule.

11. Oral dosage form, according to any of the preceding claims, characterized in that the dosage form is a tablet.

12. Oral dosage form, according to any of the preceding claims, characterized in that the dosage form is a dispersible tablet.

13. A method for treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), characterized in that it comprises orally administering an effective amount of one or more dosage forms, as defined in any of the preceding claims, to the patient.

14. Method according to claim 13, characterized in that approximately 2 mg / m2 of mirdametinib are administered to the patient twice daily.

15. Method according to claim 13, characterized in that (a) for a patient having a body surface area not exceeding 0.69 m2, the patient is initially administered 1 Petition 870250081868, dated 11 / 09 / 2025, page. 58 / 77 3 / 10 mg of mirdametinib twice daily, (b) for a patient with a body surface area of ​​0.7 to 1.04 m2, the patient is initially given 2 mg of mirdametinib twice daily, (c) for a patient with a body surface area of ​​1.05 to 1.49 m2, the patient is initially given 3 mg of mirdametinib twice daily, and (d) for a patient with a body surface area of ​​at least 1.5 m2, the patient is initially given 4 mg of mirdametinib twice daily.

16. Method according to claim 13, characterized in that (a) for a patient with a body surface area of ​​0.4 to 0.59 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (d) for a patient with a body surface area of ​​1.0 to 1.19 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily, (e) for a patient with a body surface area of ​​1.2 to 1.39 m2, the patient is initially administered 3 mg of mirdametinib twice daily, (f) for a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially given 3,5 mg of mirdametinib twice daily, and Petition 870250081868, dated 11 / 09 / 2025, page 59 / 77 4 / 10 (g) for a patient with a body surface area of ​​at least 1.6 m2, the patient is initially administered 4 mg of mirdametinib twice daily.

17. Method according to claim 16, characterized in that the patient is under 12 years of age.

18. Method according to claim 16 or 17, characterized in that mirdametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing.

19. Method, according to any one of claims 16 to 18, characterized in that mirdametinib is administered in the form of one or more dispersible tablets.

20. Method according to claim 13, characterized in that (a) for a patient having a body surface area of ​​0.4 to 0.69 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) for a patient having a body surface area of ​​0.7 to 1.04 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (c) for a patient having a body surface area of ​​1.05 to 1.49 m2, the patient is initially administered 3 mg of mirdametinib twice daily, and (d) for a patient having a body surface area of ​​at least 1.5 m2, the patient is initially administered 4 mg of mirdametinib twice daily.

21. Method according to claim 20, characterized in that the patient is at least 12 years of age.

22. Method according to claim 20 or 21, characterized in that mirdametinib is administered in the form of Petition 870250081868, dated 11 / 09 / 2025, page 60 / 77 5 / 10 one or more capsules.

23. Method according to claim 13, characterized in that (a) for a patient with a body surface area of ​​0.4 to 0.59 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (d) for a patient with a body surface area of ​​1.0 to 1.39 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily, (e) for a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially administered 3 mg of mirdametinib twice daily, (f) for a patient with a body surface area of ​​1.6 to 1.69 m2, the patient is initially given 3,5 mg of mirdametinib twice daily, and (g) for a patient with a body surface area of ​​at least 1.7 m2, the patient is initially administered 4 mg of mirdametinib twice daily.

24. Method according to claim 23, characterized in that the patient is under 12 years of age.

25. Method according to claim 23 or 24, characterized in that mirdametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof. Petition 870250081868, dated 11 / 09 / 2025, pp. 61 / 77 6 / 10 26. Method, according to any one of claims 23 to 25, characterized in that mirdametinib is administered in the form of one or more dispersible tablets.

27. Method, according to any one of claims 13 to 16, 18 to 20, 22, 23, 25 and 26, characterized in that the patient is between 2 and 15 years of age.

28. Method, according to any one of claims 13 to 16, 18 to 20, 22, 23, 25 and 26, characterized in that the patient is at least 16 years of age.

29. Method, according to any one of claims 13 to 28, characterized in that the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient, at least partially, based on its objective response rate, wherein the objective response rate is defined as a reduction of at least 20% in tumor size using central-reading MRI volumetric analysis.

30. Method according to claim 29, characterized in that in step (i), mirdametinib is selected based on a response rate of at least 70%.

31. Method for treating a human patient with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), characterized in that it comprises administering mirdametinib orally to the patient, wherein (a) for a patient with a body surface area of ​​0.4 to 0.59 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of Petition 870250081868, dated 11 / 09 / 2025, p.62 / 77 7 / 10 mirdametinib twice daily, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (d) for a patient with a body surface area of ​​1.0 to 1.19 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily, (e) for a patient with a body surface area of ​​1.2 to 1.39 m2, the patient is initially administered 3 mg of mirdametinib twice daily, (f) for a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially administered 3.5 mg of mirdametinib twice daily, and (g) for a patient with a body surface area of ​​at least 1.6 m2, the patient is initially administered 4 mg Mirdametinib twice daily.

32. Method according to claim 31, characterized in that the patient is under 12 years of age.

33. Method according to claim 31 or 32, characterized in that mirdametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing.

34. Method, according to any one of claims 31 to 33, characterized in that mirdametinib is administered in the form of one or more dispersible tablets.

35. Method for treating a human patient who has inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), characterized in that it comprises orally administering mirdametinib to the patient, wherein (a) for a patient with a body surface area Petition 870250081868, dated 11 / 09 / 2025, page. (a) For a patient with a body surface area of ​​0.4 to 0.69 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) For a patient with a body surface area of ​​0.7 to 1.04 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (c) For a patient with a body surface area of ​​1.05 to 1.49 m2, the patient is initially administered 3 mg of mirdametinib twice daily, and (d) For a patient with a body surface area of ​​at least 1.5 m2, the patient is initially administered 4 mg of mirdametinib twice daily.

36. Method according to claim 35, characterized in that the patient is at least 12 years old.

37. Method according to claim 35 or 36, characterized in that mirdametinib is administered in the form of one or more capsules.

38. Method for treating a human patient with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), characterized in that it comprises administering mirdametinib orally to the patient, wherein (a) for a patient with a body surface area of ​​0.4 to 0.59 m2, the patient is initially administered 1 mg of mirdametinib twice daily, (b) for a patient with a body surface area of ​​0.6 to 0.79 m2, the patient is initially administered 1.5 mg of mirdametinib twice daily, (c) for a patient with a body surface area of ​​0.8 to 0.99 m2, the patient is initially administered 2 mg of mirdametinib twice daily, (d) for a patient with a body surface area Petition 870250081868, dated 11 / 09 / 2025, p.64 / 77 9 / 10 from 1.0 to 1.39 m2, the patient is initially administered 2.5 mg of mirdametinib twice daily, (e) for a patient with a body surface area of ​​1.4 to 1.59 m2, the patient is initially administered 3 mg of mirdametinib twice daily, (f) for a patient with a body surface area of ​​1.6 to 1.69 m2, the patient is initially administered 3.5 mg of mirdametinib twice daily, and (g) for a patient with a body surface area of ​​at least 1.7 m2, the patient is initially administered 4 mg of mirdametinib twice daily.

39. Method according to claim 38, characterized in that the patient is under 12 years of age.

40. Method according to claim 38 or 39, characterized in that mirdametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing.

41. A method according to any one of claims 38 to 40, characterized in that mirdametinib is administered in the form of one or more dispersible tablets.

42. Method, according to any one of claims 13 to 21, 23 to 36 and 38 to 41, characterized in that mirdametinib is in the form of one or more dispersible tablets and, before administration, the one or more dispersible tablets are dispersed in water to form a suspension and, optionally, the suspension is shaken until there are no more lumps.

43. Method according to claim 42, characterized in that one or more dispersible tablets are dispersed in 5 to 10 mL of water to form the suspension.

44. Method, according to claim 42 or 43, characterized by the fact that the suspension is administered to the patient within 30 minutes of being prepared. Petition 870250081868, dated 11 / 09 / 2025, page 65 / 77 10 / 10 45. Method according to any one of claims 13 to 44, characterized in that it comprises (a) mirdametinib having a d90 of not more than 250 microns and (b) one or more pharmaceutically acceptable excipients.

46. ​​Method according to claim 45, characterized in that mirdametinib has a d50 of not more than 50 microns.

47. Method according to claim 45, characterized in that mirdametinib has a d50 of no more than 30 microns.

48. Method according to any one of claims 45 to 47, characterized in that each of the one or more dosage forms is a capsule prepared by (i) roller compaction of a mixture of mirdametinib and one or more pharmaceutically acceptable excipients and (ii) encapsulation of the compacted mixture in a capsule. Petition 870250081868, dated 11 / 09 / 2025, pp. 66 / 77

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